PROJECT SUMMARY/ABSTRACT COVID-19, the pandemic illness caused by the novel virus SARS-CoV-2, is a serious respiratory illness that has high infectivity and a mortality rate that varies from <1% to up to 20% depending on underlying risk factors. Indeed, disease severity varies markedly based on recognized clinical risk factors (age and co-morbidities). The biological underpinnings of this clinical variability are unknown but likely relate to variation in both the virus and the host response. A detailed understanding of the risk factors for severe disease, including genetic and environmental factors and the nature of the host immunological response, is essential for the development of prognostic biomarkers and effective therapies. To meet this urgent need we propose to help develop and to participate in the IMPACC multi-center longitudinal clinical study of hospitalized patients with COVID-19 and to immunophenotype participants using shared immunological methods that will be designed an carried out by core laboratories at UCSF and at other participating institutions. Our specific aims are 1) to develop a prospective observational convenience cohort of adult subjects hospitalized with known or presumptive COVID-19, 2) to use this cohort to describe the relationship between specific immunologic assessments and clinical course of COVID-19 in hospitalized patients, and 3) to implement three core laboratories at UCSF to support immunophenotyping in this multicenter cohort. These core laboratories will perform bulk RNA sequencing of blood peripheral blood mononuclear cells (PBMC), bulk metagenomic next-generation sequencing (mNGS) on endotracheal aspirate samples, and serologic phage display assays (PhIP-Seq). Successful completion of these aims will yield critical information regarding the relationship between viral load, host immunological responses, and poor clinical outcomes that are urgently needed for biomarker development and rational therapeutic targeting. In addition, the cellular samples banked in this study may directly contribute to the development of neutralizing antibodies and vaccine strategies that will be our ultimate defense against recurrence of this extraordinary pandemic. A rapid and robust scientific and medical response of the type proposed by the NIAID and the academic community in this consortium is an essential element of a broad response required to protect the health and well-being of all individuals, our health care system, and the broader social structures that maintain global health and welfare.